Schizophrenia is a complex multifactorial syndrome of possibly more than one disease involving billions of neurons, glial cells, and brain tissues. Within the last decade biochemical research on schizophrenia has pivoted around the dopamine hypothesis. Observations that amphetamines which enhance dopamine (DA) activity produce syndromes indistinguishable from schizophrenia provide support for the theory. Yet other neurotransmitters are involved; imbalances in norepinephrine, serotonin and other catecolamines have been reported and as a result the dopamine hypothesis has been modified. Basic in vitro cell biology research into this common mental disorder lags far behind in vivo psychopharmacological studies. Preliminary experiments outlined in this proposal are designed to test the hypothesis that one of the basic structural defects in neurons exposed to drugs which induce schizophrenia is altered regulation and organization of the cell cytoplasm and cytoskeleton. Neurotransmitters synthesized in the cell are transported to sites of utilization by the cytoskeleton of the axon. Synthesized neurotransmitters are packaged, stored, and released from synaptic vessicles by exocytosis. The organizing/regulatory role of the cytoskeleton in synaptosome membrane recycling after drug intoxication has not been defined and is worthy of investigation. Major methodologies include utilizing neuronal cell cultures in correlative scanning electron (SEM) and transmission electron (TEM) microscopy. Specific aims are (a) to culture human neuroblastoma SK-N-SH and SK-N-MC cells in vitro; (b) to expose cells to d-amphetamines at 10-4-10-8M from 1 hour to 3 months (daily/or intermittently) (c) to use correlative scanning and transmission electron microscopy to study whole cells and triton extracted cytoskeletons to characterize surface topographical and ultrastructural changes in the skeleton and cytoplasm drug exposed neurons. These experiments will gather preliminary ultrastructural data on alterations in neurons exposed to amphetamines. If successful this one year study will provide foundation for longer term (3-5 years) objectives of using monoclonal antibodies immunoelectron microscopy to characterize IF organization and, biochemically quantitating neurotransmitter levels and correlating levels with cytoskeletal structural integrity. This pilot study will document ultrastructural changes in neurons and may plant seeds for future studies on the cytoskeleton of neurons exposed to d-amphetamines.